Abstract

Proper craniofacial development begins during gastrulation and requires the coordinated integration of each germ layer tissue (ectoderm, mesoderm, and endoderm) and its derivatives in concert with the precise regulation of cell proliferation, migration, and differentiation. Neural crest cells, which are derived from ectoderm, are a migratory progenitor cell population that generates most of the cartilage, bone, and connective tissue of the head and face. Neural crest cell development is regulated by a combination of intrinsic cell autonomous signals acquired during their formation, balanced with extrinsic signals from tissues with which the neural crest cells interact during their migration and differentiation. Although craniofacial anomalies are typically attributed to defects in neural crest cell development, the cause may be intrinsic or extrinsic. Therefore, we performed a phenotype-driven ENU mutagenesis screen in mice with the aim of identifying novel alleles in an unbiased manner, that are critically required for early craniofacial development. Here we describe 10 new mutant lines, which exhibit phenotypes affecting frontonasal and pharyngeal arch patterning, neural and vascular development as well as sensory organ morphogenesis. Interestingly, our data imply that neural crest cells and endothelial cells may employ similar developmental programs and be interdependent during early embryogenesis, which collectively is critical for normal craniofacial morphogenesis. Furthermore our novel mutants that model human conditions such as exencephaly, craniorachischisis, DiGeorge, and Velocardiofacial sydnromes could be very useful in furthering our understanding of the complexities of specific human diseases.

Schematic representation of the spatial distribution of 140 microsatellite markers (red) that are distinct between C57BL/6;129S1/Sv and FVB/NJ and were used to map the gross chromosomal location of mutations in each of the ENU generated mouse lines. The numeric designation representing the precise position for each microsatellite marker can be found in Sandell et al. (2007).

Definitive chromosomal position of mutations identified in individual ENU mutant lines or the refined chromosomal region to which they have been currently been mapped. Arrowheads indicate the precise chromosome position of the mutation identified in trex, (T.rex), sot (sottile tubo), and gri (grimace) lines. Parentheses are indicative of the broad region of individual chromosomes to which pal (palloncino), mul (mullet), orv (orvieto), sno (snouty), arc (arco piccolo), and wig (wiggable) have been currently mapped.